Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) and related azetidine and proline derivatives are competitive inhibitors of angiotensin-converting enzyme (ACE) that block the conversion of angiotensin I to angiotensin II. Captopril and its derivatives are used as antihypertensive agents in treating most forms of hypertension (U.S. Pat. No. 4,046,889, Ondetti et al, 1977; Thind, 1990; Cushman et al, 1991. Migdalof et al. 1984; Materson et al, 1994)
Captopril contains a free sulfhydryl group and is quite stable in aqueous solution. However, in the blood or plasma of mammals, including humans, it is rapidly oxidized to its disulfide dimer and is involved in other disulfide exchange reactions. Captopril was found to bind covalently but reversibly to plasma proteins, cysteine, and glutathione (Migdalof et al, 1984)
Unfortunately, rather high doses of captopril are required to reduce blood pressure. This phenomenon may be because most of the captopril is used up in reactions with serum protein, to reduce —S—S bonds in proteins, and to form the mixed disulfide of protein-captopril. Thus, only a small amount of free captopril, or captopril recycled from the mixed disulfide with proteins, glutathione, and cysteine, remains for inhibiting ACE. Therefore, larger amounts of captopril are required as compared with other non-thiol containing ACE inhibitors. This may explain the discrepancy between the in vitro and in vivo activity of captopril.
It has recently been shown that allicin (dithiosulfinate), a product of crushed garlic, which the present inventors prepared semi-synthetically (international patent WO 97/39115), also possesses antihypertensive properties. Other studies reported the remedial effects of allicin on cardiovascular risk factors, mainly on serum cholesterol, triglycerides levels, as well as lipoprotein balance, streak formation, and thrombogenesis in animals and in humans (Augusti et al, 1974; Eilat et al, 1995; Lawson, 1998; Abramovitz et al, 1999). Lipid lowering effect is one of the earliest established properties of garlic preparations, which also have a hypotensive effect as shown by Loeper et al (1921), which effect was confirmed by others in humans (Damrau, 1941; Petkov, 1979) and in animals (Chanderkar et al, 1973; Banerjee, 1979; Malik et al, 1981; Foushee et al, 1982; Ruffin et al, 1983; Auer et al, 1990; Aqel et al, 1991).
Two possible mechanisms for the action of allicin have been suggested. One involves the antioxidant activity of allicin, while the other mechanism is that the particular structure of allicin, as activated disulfide, makes it a good candidate for interaction with the SH groups of proteins and low molecular weight thiols. Allicin, which is a very reactive compound, also disappears within a few minutes after being mixed with blood, due to its fast penetration through cell membranes, and its reaction with free thiol containing compounds, mainly reduced glutathione (GSH). From studies conducted by the present inventors, Rabinkov et al (1998) and Miron et al (2000), it appears that the active principal of allicin is the allylmercapto moiety (AM), which blocks thiol containing enzymes or reacts as a very efficient antioxidant.